Are the hopes of a direct conversion of astrocytes into neurons dashed?

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In 2013, Xiang-Dong Fu of the University of California, San Diego, and colleagues found that deleting a single gene converts a variety of cells, including fibroblasts, directly into neurons. This procedure represents one of the simplest methods of generating neurons to date. Since it does not require any foreign DNA, it can bring in-vivo direct cells conversion closer to the clinic.

Cellular reprogramming technology, including the generation of induced pluripotent stem cells, had raised hopes that scientists might one day replace dying cells with new ones derived from patient's healthy tissues. New presentations in 2019 had really made people think that a clinical solution for neurodegenerative diseases like Parkinson's, Alzheimer's or ALS (Charcot's disease) was at hand.

Fu's group proceeded by injecting directly into the substantia nigra of mice, an adeno-associated virus (AAV) carrying an RNA that inhibited PTBP1. To mark infected astrocytes, the vector they used included a fluorescent tag that could only be activated in cells infected with the virus (because it was under the control of the GFAP promoter). Researchers reported that fluorescent cells carrying neural markers formed connections with nearby striatum and reversed motor deficits in an animal model of Parkinson's disease. Obviously we could already be wondering why AAV viruses would only infect astrocytes, and not other cells and among these, neurons.

Indeed, several recent studies suggest that the apparently converted astrocytes would in fact have been neurons. These recent studies have used different cell lineage mapping approaches to label astrocytes. This type of lineage can be studied by marking a cell (with fluorescent molecules or other traceable markers) and following its progeny after cell division. In fact, it is a method quite similar to that used by the San Diego group.

Two of the studies, published in Cell Reports on June 14, reported that Müller's glia (a source of retinal stem cells that can replenish neuronal loss and restore vision) failed to convert into neurons when PTBP1 was deleted (Xie and al., 2022; Hoang et al., 2022). Two others – one published in Life on May 10 and the other published on bioRxiv on May 13 – came to similar conclusions with astrocytes in the substantia nigra and striatum (Chen et al., 2022; Yang et al ., 2022).

Their findings are consistent with a similar report published last year (Wang et al., 2021). Some have also found GFAP promoter expression in neurons, giving the mistaken impression that they were ancient astrocytes.

We can ask ourselves some serious questions, for example why the scientific community did not express as soon as the 2013 announcement was made, the fairly obvious fact that astrocytes were probably not the only ones to be infected, why did they wait 9 years to highlight this point?

Another question concerns the cell lines, these are different in the different studies, the cells are at different stages of maturation, and their phenotype is very different from that of astrocytes, so can we really draw general conclusions?

In addition, Müller's glia are derived from the development of two distinct populations of cells, which are we talking about in these new studies? Finally, they are the only retinal glial cells that share a common cell line with retinal neurons. From a certain point of view Müller's glia are neurons not astrocytes, and therefore this greatly diminishes the value of the analyzes carried out, but this should be known to scientists who have done these contradictory studies?

In response to these and other studies that challenge data for conversion of astrocytes to neurons, Fu recognized that some expression of the GFAP promoter occurs in neurons infected with AAV viruses. For him, about 5% of cells expressing AAV genes soon after infection were neurons. Yet this percentage seems very low.

On the other hand, Fu said that lineage tracing experiments performed in the new studies may have preferentially marked mature Müller cells, leaving open the possibility that the conversion of more immature cells into neurons may have been missed. .

Finally, knocking out PTBP1 effectively restored dopamine levels and boosted motor function in a mouse model of Parkinson's disease. If not by the creation of new neurons, what could e

Hepatitis E virus may be associated with neurodegenerative disorders in the elderly

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Neurodegenerative diseases are often sometimes to a virus, in particular HERV-K, but this has never been demonstrated convincingly.

Hepatitis E virus (HEV) infections are not limited to the liver but can also affect other organs. Several neurodegenerative diseases including Guillain-Barré syndrome, neuralgic amyotrophy, meningitis, have been observed in the context of hepatitis E. Additionally, HEV infection has been observed with other neurological diseases, such as encephalitis, myelitis, and Bell's palsy. Patients may have normal liver function tests, which can often mislead doctors into inferring that there is no HEV infection. enter image description here

Case-control studies are a type of epidemiological study. They have often been used in the study of rare diseases where little is known about the association between the risk factor and the disease of interest.

Case-control studies are used to identify factors that may contribute to a disease by comparing subjects who have that disease (the “cases”) with patients who do not have the disease but are otherwise similar (the “controls”).

In this case-control study, scientists from Spain assessed the association between serum antibodies against the hepatitis E virus and neurodegenerative disorders of the central nervous system in older people with dementia.

The presence of anti-HEV antibodies was related to a higher adjusted odds ratio of having neurodegenerative disorders by neuropathological diagnosis and clinical/neuropathological diagnosis.

Furthermore, serum anti-HEV antibodies were directly linked to neuropathological injury and a higher likelihood of having Alzheimer-like pathology.

The scientists conclude their article by assuming that the presence of anti-HEV antibodies was indeed linked to a higher risk of neurodegenerative disorders and neuropathological lesions in the elderly.

However, the reader should exercise caution. Case-control studies are observational in nature and do not provide the same level of information as randomized controlled trials. The results can be distorted by other factors, sometimes significantly.

Flavonoid and chromone-rich extract from Euscaphis Konishii Hayata leaf attenuated alcoholic liver injury in mice.

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Contrary to appearances, there is some links in this post with neurodegenerative diseases. Alcoholic liver injury are one kind of cellular stress. All drugs that can treat cellular stress, and especially Endoplasmic Reticulum (ER) stress, can probably be used against most common neurodegenerative diseases. The same is true for drugs with free radicals scavenging activity.

Euscaphis konishii Hayata is a traditional medicinal plant in China, and its leaves are usually used to make dishes for hepatic or gastrointestinal issues by Chinese She nationality. Hepatocellular carcinoma (hepatoma) is the most common type of primary liver cancer in adults. Hepatocellular carcinoma causes 662,000 deaths worldwide per year about half of them in China.

Pharmacological analysis showed that E. konishii leaves contain high levels of flavonoids and chromones with favorable anti-hepatoma effect. 8 flavonoids and 2 chromones were recognized in the chromone-rich extract. Chromones are found throughout the plant kingdom, where they serve as essential components of a number of structural polymers, provide protection from ultraviolet light, defend against herbivores and pathogens, and also mediate plant-pollinator interactions as floral pigments and scent compounds.

Alcohol-fed mice disease model were used to assess the hepatoprotective effects of these chromone-rich extract.

Chromone-rich extract represented strong free radicals scavenging activity in vitro. With oral administration, chromone-rich extract dose-dependently decreased the serum levels of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase in alcohol-fed mice.

Chromone-rich extract gradually increased the activity of superoxide dismutase and glutathione peroxidase in the alcohol-treated liver tissues. Chromone-rich extract also alleviated the hepatic inflammation, inhibited the hepatocyte apoptosis and lessened the alcohol-induced histological alteration and lipid accumulation in the liver tissues.

Chromone-rich extract administration inhibited the overexpression of endoplasmic reticulum chaperones signaling and unfolded protein response pathways to defense the ER-induced apoptosis. Pretreatment with chromone-rich extract also restored the mitochondrial membrane potentials andadenosine triphosphate levels, which in turn suppressed the Cytochrome C release and mitochondria-induced apoptosis.

Chromone-rich extract conferred great protection against alcoholic liver injury, which might be associated with its viability through suppressing reactive oxygen species stress and hepatocyte apoptosis.

It may be possible they also have positive effects in neurodegenerative diseases.

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Proteins alterations observed in neurodegenerative disorders could be linked to the minimization of proteomic costs

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Aging is an important risk factor for neurodegenerative disorders (neurodegenerative disorders), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD ).

Protein synthesis has historically been described as decreasing with age, although not all studies agree and often point to high organ and tissue variability. Protein degradation is also commonly described as compromised in aging

Analysis of brain protein levels in the physiologically aged brain, however, showed only minor changes in protein abundance in the older adult brain compared to the young adult brain. However, a recent theory indicates that the alterations observed in neurodegenerative disorders could be linked to the minimization of proteomic costs, reflecting a new prioritization of bioenergetic costs, which would preserve the most "expensive" proteins in energy from the aged brain while replacing more easily metabolically less expensive proteins.

To test this theory, it is interesting to study protein turnover, which regulates the balance between protein synthesis and degradation, because it could be particularly affected by aging and could lead to changes prelude to neuropathology. The turnover of proteins begins with their destruction, the catabolism of proteins is a key function of the digestive process. The amino acids resulting from these proteins thus degraded can be transformed into fuel for the Krebs cycle/citric acid (TCA).

Researchers led by Anja Schneider of the German Center for Neurodegenerative Diseases in Bonn and Eugenio Fornasiero of the University Medical Center Göttingen, both in Germany, measured the half-lives of more than 3,500 proteins in mouse brain. They found an average increase of 20 percent with age. **enter image description here**

For Alzheimer's disease, these life-extending proteins included:

  • the group of Tau proteins (MAPT)
  • ADAM10 which is correlated with the appearance of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's disease.
  • DBN1 A decrease in the amount of this protein in the brain has been implicated as a possible contributing factor in the pathogenesis of memory impairment in Alzheimer's disease.
  • CTSDs which are implicated in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer's disease.

For Parkinson's disease, they included:

  • Alpha-synuclein, a protein which in humans is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and the subsequent release of neurotransmitters. It is abundant in the brain, while smaller amounts are found in the heart, muscle, and other tissues. In the brain, alpha-synuclein is found primarily in the axon terminals of presynaptic neurons.

    Alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. These disorders are known as synucleinopathies.

  • PARK7, Under oxidative conditions, the deglycase protein DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity, thus functioning as a redox-sensitive chaperone and as an oxidative stress sensor. The functional protein DJ-1 has been shown to bind to metals and protect against metal-induced cytotoxicity of copper and mercury. Defects in this gene cause early-onset autosomal recessive Parkinson's disease

For ALS, they included:

  • TUBA4A, The alpha-4A chain of tubulin is a protein which in humans is encoded by the TUBA4A gene. This gene has only rarely been associated with ALS. Overall, ALS-related genes can be categorized into four groups based on the cellular pathways in which they are involved: (1) protein homeostasis; (2) homeostasis and RNA trafficking; (3) cytoskeletal dynamics; and (4) mitochondrial function.

    The reason TUBA4A might be associated with ALS is that motor neurons and skeletal muscle cells are known to be the largest cells in the human body. The significant length of these cells makes them highly dependent on the correct architecture of the cytoskeleton, the integrity of which is essential for the axonal transport necessary to maintain the integrity of synapses. Several mutations in the tubulin beta-4A (TUBA4A) gene destabilize microtubules by impairing repolymerization, likely contributing to axonal degeneration in MN.

  • SOD1, whose protective role against oxidative stress has been well studied, but whose mutations were previously only associated with 25% cases of familial ALS.

Conclusion The authors of this article observed a previously unknown alteration in proteostasis that is correlated with parsimonious protein turnover with high biosynthetic costs, revealing a global metabolic adaptation that preludes neurodegeneration.

However, nothing in this study explains how malformed, poorly localized proteins might appear. This study only shows a correlation between the half-life of proteins and certain neurodegenerative diseases.

Their results suggest that future therapeutic paradigms, aimed at addressing these metabolic adaptations, may be able to delay the onset of neurodegenerative disorders.

Among these we could mention certain factors related to metabolism which determine the half-life of proteins such as pH and temperature. It is well known that aging cells have an increasing pH: They become basic. when the daughter cells come from an aging mother cell, the daughter's age is "reset". A parent cell becomes less acidic as the parent cell ages. Daughter cells, on the other hand, have very acidic vacuoles.

Alterations in metabolic biomarkers and their potential role in amyotrophic lateral sclerosis.

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Accumulating evidence suggests defective energy metabolism in ALS patients, which contributes to weight loss and a poor prognosis.

Lipid metabolism disorders have been widely reported in patients with ALS, presenting with hypercholesterolemia, hypertriglyceridemia, and other mixed dyslipidemias. Leptin, an adipokine, plays a neuroprotective role in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Nagel et al. suggested that leptin concentrations were positively correlated with the survival rate in ALS patients, indicating protective effects of leptin in patients with ALS.

Serum leptin concentration is strongly correlated with body weight or BMI, which was also confirmed in this study written by scientists from Chinese Academy of Medical Sciences. And higher body weight and BMI have been found to be associated with a lower risk of ALS and better prognosis in ALS patients.

Adipokines are a group of factors released or secreted by adipose tissue and have many physiological functions, such as fat distribution, energy expenditure, appetite and satiety regulation, insulin secretion and sensitivity, and inflammation.

Previous studies on the biological functions of adiponectin provide some evidence that adiponectin is beneficial in ALS. As one of the most abundant adipokines secreted by adipocytes, adiponectin functions in multiple physiological processes, including insulin sensitization, glucose regulation, lipid metabolism, and anti-inflammatory and antiapoptotic activities.

Fifty-two subjects were recruited between October 2020 and January 2022 among patients newly diagnosed with ALS in the Neurology Department of Peking Union Medical College Hospital. The study also included 24 healthy participants to compare adipokines and other metabolic biomarkers.

When comparing adipokines in patients and controls, the authors, found significant differences in the levels of adiponectin, adipsin, resistin, and visfatin between the two groups.

ALS patients had higher levels of adipokines (adiponectin, adipsin, resistin, and visfatin) and other metabolic biomarkers [C-peptide, glucagon, glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide, and plasminogen activator inhibitor type 1] than controls.

Leptin levels in serum were positively correlated with body mass index, body fat, and visceral fat index.

Adiponectin was positively correlated with the visceral fat index and showed a positive correlation with the ALSFRS-R and a negative correlation with baseline disease progression.

Lower leptin and adiponectin levels were correlated with faster disease progression. After adjusting for confounders, lower adiponectin levels and higher visfatin levels were independently correlated with faster disease progression.

Berberine, an isoquinoline alkaloid, has been shown to increase adiponectin expression, which partly explains its beneficial effects on metabolic disturbances. Mice fed the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both omega-3 fatty acids, have also shown increased plasma adiponectin. Curcumin, capsaicin, gingerol, and catechins have also been found to increase adiponectin expression.

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ROS and Endoplasmic Reticulum Stress in Pulmonary Disease.

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Here is an interesting article, that reviews misfolded proteins in lungs. In our body, cells while available in ~200 types, share common characteristics, so it's not surprising that diseases that affect brain cells, also affect other organs. Misfolded and mislocated proteins are associated with most neurodegenerative diseases, yet we do not know if they are a cause or a consequence of the disease.

Lung disease is one of the leading causes of morbidity and mortality worldwide. Current studies show that although lung diseases possess unique pathophysiology and specific clinical manifestations, they still tend to exhibit common features, including accumulation of reactive oxygen species and disturbances in proteostasis leading to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER).

The article is not really precise on these disruptions of proteostasis, how they emerge, nor how they cause the accumulation of unfolded or misfolded proteins. One can however imagine that the long way by which a protein is elaborated and which by the making of a messenger RNA, its use by a ribosome (stuck to a membrane of the ER) to generate an unfolded protein, its folding in the ER then its dispatch in vesicles on the operating site by the Golgi apparatus, is susceptible to many malfunctions.

The cellular response to proteostasis dysfunction is called UPR. This is a set of poorly understood mechanisms that globally decrease the production of proteins for the duration of the stressful event, but whose involvement in neurodegenerative diseases is increasingly suspected.

In fact, decreasing the production of proteins does not really help the survival of the biological host of these cells, these proteins are necessary for life, and each is involved in all kinds of biological reactions. The triggering of UPR is therefore a guarantee of future health problems for the host.

When the adaptive unfolded protein response fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to disruption of ER integrity and apoptosis, referred to as ER stress.

ER stress primarily includes accumulation of misfolded and unfolded proteins in the lumen and disturbance of Ca balance. ROS mediate several critical aspects of the ER stress response.

Here the authors summarize the latest advances in UPR and ER stress in the pathogenesis of lung disease and discuss potential therapeutic strategies aimed at restoring ER proteostasis in lung disease.

Hopefully this kind of publication will help to cross-fertilize research in UPR mechanisms in brain diseases, and they may also help shed a new look on muscle wasting in ALS, not as a consequence of motor neuron disease, but as an independent event occurring in a more global context.

Read the original article on Pubmed

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Circulating Lipids and the Risk of TDP-43 Related Disorders

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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two distinct degenerative disorders with overlapping pathology, including the presence of TDP-43 aggregates in nearly 50% of patients with FTD and 98% of all patients with ALS.

The BMI and circulating lipids are complex traits that have been previously associated with ALS, and to a much lesser extent with FTD. The BMI seems to be delineating the clinical form along the spectrum, with the smaller BMI at the ALS end and the highest in the FTD end of the spectrum.

Scientists from Instituto de Investigación Sanitaria San Carlos (IdISSC), and Universidad Complutense de Madrid in Spain, hypothesized that some of the genetic variants affecting body's lipid metabolic traits could be associated with particular clinical forms of TDP-43 proteionopathies within the spectrum of disorders of FTD and ALS.

To assess this hypothesis, the authors used an analytical tool known as Mendelian randomization analysis (MR) of 2 samples (2SMR), which allows for the identification of overlapping genetic variants betthe authorsen several risk factors and the disease of interest.

Many epidemiological study designs are limited in the ability to discern correlation from causation. Mendelian randomization is a statistical method using variation in genes (alleles) to reduce the impact of confounding factors, which often mislead the interpretation of results from epidemiological studies. It relies on the fact that groups of individuals defined by genetic variation associated with an exposure should be largely unrelated to the confounding factors. Yet using only one set of data is not without its own problems, so scientists prefer to use two sets of independant data.

Two-sample Mendelian randomization refers to the application of Mendelian randomization methods to summary association results estimated in non-overlapping sets of individuals. These data can be obtained from the published literature, typically from summary results provided by consortia of genome-wide association studies (GWAS), or estimated directly from individual-level participant data.

The scientists from Madrid conducted two independent studies in parallel to evaluate the effect of genetically predicted body complexion and circulating lipids on the risk of FTLD TDP subtype and on ALS and compared their effects in these two TDP-43 related diseases that belong to a spectrum of disorders.

The authors found that body trunk mass and triglycerides levels could be more relevant for the risk of FTLD TDP subtype, and on the contrary, the levels of LDL cholesterol, and possibly linoleic and omega 6 fatty acids, play a more important role in the risk of ALS. enter image description here Moreover, they identified two genetic variants shared in the two studies conducted on FTD and ALS. These two variants are located in two genes that encode proteins with role in RNA metabolism which is a well-documented pathological mechanism operating in these disorders.

Though the significantly associated circulating lipid traits were different between FTD and ALS, the researchers could identify a common significant genetic variant in the HNRNPK gene in both the diseases. This gene is widely expressed in neuronal tissue and encodes for the hnRNP K protein. Similar to TDP-43, which is also a family member of hnRNP proteins, this protein binds to RNA and has a role in RNA processing and maturation. This protein is altered in models of ALS with TDP43 mutation, and recently, it has been found mislocalized in patients with FTLD.

Curiously, it has been shown that hnRNP K phosphorylation controls the aggregation of TDP-43 in the cytosol. These findings suggest that HNRNPK could be a potential molecular causal link between the lipid metabolic alterations and ALS/FTD spectrum of disorders.

In conclusion the scientists demonstrated that lipid metabolic genetic variation is important pathological mechanism contributing to these multifactorial complex disorders etiology. In particular, their study suggests that higher LDL cholesterol and fatty acid levels could potentially have a causal role in the risk of ALS.

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ALS, cellular stress and Inflectis' new drug.

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InFlectis BioScience received Orphan-Drug Designation from the U.S. Food and Drug Administration (FDA) for its investigational treatment for Amyotrophic Lateral Sclerosis (ALS), IFB-088.

IFB-088 or Sephin-1, is an improved version of Guanabenz, a medication to treat hypertension. enter image description here In a phase II clinical trial in Italy, Guanabenz offered a comparable level of protection to AMX0035 for people but specifically for patients with a bulbar onset.

IFB-088 as act as AMX0035 on the cellular stress response but in an different manner. IFB-088 as several action,

  1. It reduces mitochondrial stresses in ALS.
  2. IFB-088 is prolonging the protective effect of the Unfolding Protein Response (which trigger Integrated Stress Response) to prevent the production of new misfolded protein and increasing the stress response gene transcription to increase the cellular chaperones until the ER stress is resolved.

After the failure of many ALS drugs including Arimoclomol, and Biogen's two genetiic therapies for SOD1 and C9orf72, scientists are searching for new paradigms.

Research on ER cellular stress offers a clear mechanism of action, something lacking for almost all proposed drugs: When a new protein is built by a ribosome under the direction of mRNA, this protein is "flat", it has not acquired its final shape. This contorted shape makes it acquire new chemical properties.

Folding proteins is achieved in the Endoplasmic Reticulum (ER). Ribosomes are close to the ER so it's easy for proteins to enter the ER which is a very complex structure. At the exit of the ER folded proteins are sent to their final destinations by the Golgi apparatus.

If the ER is not working properly, then proteins built by ribosomes will not be able to be folded and will accumulate at the entrance of the ER, hence aggregates of misfolded, mislocated proteins.

While Sodium phenylbutyrate suppresses the cellular stress, Sephin-1 increases it. It is possible the two drugs might be useful at different stages of the disease course and for different populations.

Both drugs relative efficiency indicates that cell stress responses in neurodegenerative diseases are to be studied with much more attention than done previously.

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Blood DNA methylation in older people with dementia

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Neurodegenerative diseases mainly affect the elderly. These diseases are characterized by the production of aggregates of misfolded, mislocalized proteins. One might think that there is a causal link between aging and this production of abnormal proteins. This link could be related to DNA methylation or genome instability, two phenomena associated with aging and having an impact on protein production. enter image description here The strong effect of age on DNA methylation levels has been known since the late 1960s. Horvath hypothesized that DNA methylation age measures the cumulative effect of a system epigenetic maintenance.

The sources of genome instability have only recently begun to be elucidated. Since endogenous DNA damage (caused by metabolism) is very common, occurring on average more than 60,000 times per day in human cell genomes, any reduced DNA repair is likely an important source genome instability.

For example, dogs lose about 3.3% of their heart muscle cell DNA every year, while humans lose about 0.6% of their heart muscle DNA every year. These figures are close to the ratio of the maximum longevities of the two species (120 years against 20 years, a ratio of 6/1).

DNA methylation could therefore explain the interindividual variability observed in the development of dementia and cognitive disorders. However, the importance of epigenetic alterations in explaining their etiology is unclear because little is known about when they appear.

In a recent publication, the authors longitudinally using Illumina MethylationEPIC chips, analyzed the peripheral blood methylomes of cognitively healthy older adults (>70 years), some of whom later developed dementia while others remained healthy. The methylome is the set of nucleic acid methylation modifications in the genome of an organism or in a particular cell.

The scientists tested 34 people at the pre-diagnosis stage and at a 4-year follow-up at the post-diagnosis stage (total n=68).

Their results show multiple alterations in DNA methylation linked to dementia status, particularly at differentially methylated regions.

The authors also validate the previously reported epigenetic alteration of HOXB6 and PM20D1 (associated with Alzheimer's disease). They show that most of these regions are already altered at the pre-diagnosis stage of people who then develop dementia.

In conclusion, their observations suggest that dementia-associated epigenetic patterns are already present before diagnosis, and therefore may be important in the design of epigenetic biomarkers for peripheral tissue-based disease detection.

In addition, one could imagine that the therapeutic use of Yamanaka factors (Myc, Oct3/4, Sox2 and Klf4) could lead to an improvement in this type of pathology. This has recently been recently tested using lines of mice genetically modified to produce the Yamanaka factors.

It seems considerably more difficult to perform successful gene therapy on humans, while people with dementia often have a very low life expectancy at the time of their diagnosis.

Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis

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It's as if our being was a chimera of two organisms, one would be the body and the other would be the central nervous system (CNS).

The CNS blood circulatory system is separated from the body system by nearly impervious barriers except for very small molecules. The CNS has it's own immune system (astrocystes), it has it's own clearing system known as the glymphatic system.

Multiple lines of evidence suggest possible impairment of the glymphatic system in several neurodegenerative diseases. This makes sense in a field where little makes sense. If those diseases are characterized by misfolded proteins clumps, at least in extracellular medium as in Alzheimer, then the question of the quality of the clearance mechanism is of utmost importance.

To investigate this, scientists used in vivo magnetic resonance imaging (MRI) to assess glymphatic function early in the course of amyotrophic lateral sclerosis (ALS), in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43, mimicking the key pathology implicated in ALS.

Recent evidence points to self-propagation of TDP-43 misfolding, either by the circulatory system, cell-to-cell contact, or via the interstitial or cerebrospinal fluids (CSF).

The glymphatic system is largely dormant during wakefulness but highly active during sleep, working to clear waste byproducts from the brain through the flow of CSF.

Preclinical studies have shown that amyloid-β, a protein implicated in Alzheimer’s disease, is cleared from the brain by the glymphatic system and that in aged mice, amyloid-β clearance is dramatically slowed.

As the prevalence of ALS also increases with age, sleep disturbances are exceedingly common in ALS and given that a single night of sleep deprivation can result in amyloid-β accumulation linked with Alzheimer’s disease, the authors hypothesized that glymphatic clearance is also impaired in ALS.

Their results demonstrate that the TDP-43 mice, in addition of usual symptoms of ALS, exhibited significantly altered glymphatic function very early in the disease course.

Yet the scientists didn't try to verify if the mice glyphatic function would be restored if the mice were feed again with doxycycline.

The authors do no attempt either to explain the relation between the genetically forced expression of TDP-43 in cytoplasm and induction of reduced glymphatic function. Indeed what would be more interesting is a proof that a reduced glymphatic function results in accumulation of misfolded proteins in cytoplasm.

So this article does not bring much additional knowledge, yet if sleeping helps removing the misfolded protein clumps, one could imagine that sleep drugs could help to manage ALS.

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